5qNCA (LOC51780): A candidate tumor suppressor gene in leukemia

Deletions of the long arm of chromosome 5 are found in acute myeloid leukemia and myelodysplasia. It is generally believed that the deletion leads to the loss of a tumor suppressor gene (TSG) and there is good agreement that the consistently deleted segment is located at 5q31. Our overall goal is to study del(5q), to find the gene which leads to transformation of myeloid cells.;One objective was to prepare a high resolution transcript map for the portion of the deleted region as the rest was mapped by others. We selected the radiation hybrid (RH) approach since the sequence for the interval was not available at the time and this is a sequence independent method. We localized 9 expressed sequences, including 4 known genes and five ESTs which might represent new genes. ESTs stsg8723 and WI-17966 were analyzed as prospective novel TSGs and we deduced that they are not real genes.;The second objective was to evaluate a selected candidate gene 5qNCA (LOC51780) for somatic mutations, and predicted function which is consistent with a TSG. We sequenced 5qNCA in 14 leukemia samples with del(5q) and found four single nucleotide polymorphisms and one substitution. This substitution (found in KG-1 cell line) was not found in additional 104 alleles, and may be a true somatic mutation.;The third objective was to establish if the mutation found in 5qNCA, results in functional inactivation consistent with a TSG. Sequence analysis predicts that 5qNCA contains the nuclear receptor binding motifs, a zinc finger, and a JmjC domain in the C-terminal half, where it is highly homologous to Hairless (HR), a thyroid hormone receptor co-repressor. This suggested that 5qNCA might interact with retinoic acid receptor (RAR) because of the important role RAR plays in hematopoiesis. We found that 5qNCA inhibits RARalpha-mediated transcription in the presence of ATRA. Both the native and KG-1 mutation forms of 5qNCA show a similar level of RARalpha co-repression, showing that the mutation does not alter this activity. However, deletions of the N-terminus fail to repress RARalpha, even though the HR-homology regions are intact. These results suggest 5qNCA plays a role in neutophil differentiation by forming a complex with RARalpha to downregulate RAR target genes. We conclude that 5qNCA is a co-repressor of RARalpha which probably has a role in normal hematopoiesis, although a causal role in leukemia has not been established.